Official Title

A Phase 2a Study to Evaluate the Safety and Tolerability of OCR-002 (Ornithine Phenylacetate) in the Treatment of Patients With Acute Liver Failure

Brief Overview

This Phase 2a clinical study is designed to provide data on OCR-002 in patients with acute
liver failure/acute liver injury (ALF/ALI) in regard to:

- safety and tolerability;

- metabolism of the compound to glutamine and phenylacetylglutamine (PAGN);

- its effect on circulating ammonia levels and neurological function in patients with and
without impaired renal function after continuous infusion at different infusion rates.

Subjects will receive up to 120 hours (5 days) of drug infusion, followed by a 30 day
follow-up visit post infusion. It is anticipated that this early safety and tolerability
study, with appropriate PK/PD data, will lead to a development program for the use of
OCR-002 in the treatment of hyperammonemia either due to ALF or possibly other liver
conditions. The hypotheses are:

Summary

There is strong experimental and clinical rationale for the use of ammonia-lowering
therapies in ALF. Ammonia is normally produced in the gut and transformed by the liver into
urea. As the liver fails, ammonia increases in the systemic circulation and enters into the
brain. The result of a rapid rise in ammonia or related compounds in the cerebral
circulation is hepatic encephalopathy (HE), a reversible neuropsychiatric condition that
ranges in severity from mild impairment in attention, to delirium, the development of
cerebral edema, coma and death. This is a Phase 2a, multi-center, open-label study,
conducted in two cohorts in patients diagnosed with acute liver failure/acute liver injury
(ALF/ALI) who meet inclusion/exclusion criteria. This study is designed to provide data on
OCR-002 with regards to

- the effect on circulating ammonia levels in patients with acute liver failure with and
without impaired renal function at different doses after single and continuous infusion

- safety and dose tolerability as well as

- providing data on the metabolites, glutamine and phenylacetylglutamine in this patient
population.

It is anticipated that this early efficacy, safety, tolerability,
Pharmacokinetic/Pharmacodynamic (PK/PD) and dose-ranging study will lead to a Phase 3
development program for the use of OCR-002 in the treatment of hyperammonemia due to ALF. No
clinical outcome measures will be formally studied because of the small sample size.

Participant Eligibility

Inclusion Criteria:

1. Men and women, ages 18-65 (have not reached their 66th birthday).

2. Acute liver failure, defined as the development of coagulopathy (International
normalized ratio [INR] ≥1.5) with encephalopathy in a patient with no prior history
of liver disease, with onset of symptoms within 28 days of the inciting event.
Patients may have either a history of acetaminophen overdose (defined as >4 g/day
within 7 days of presentation) and/or detectable acetaminophen levels in the serum,
with a pattern of liver function tests typical for acetaminophen toxicity (bilirubin
< 10 mg/dL and alanine aminotransferase (ALT) ≥1000 IU/L), or a diagnosis of
hepatitis A, hepatitis B, drug-induced liver injury, autoimmune hepatitis or
indeterminate cause based on standard criteria.

3. ALI patients may also be enrolled (those meeting the above criteria plus coagulopathy
(INR ≥ 2.0) and no evidence of encephalopathy)

4. Written informed consent from the patient (ALI) or patient's legally authorized
representative or family member if he/she is considered encephalopathic (ALF).

9. History of malignancy that has not been cured or any cancer in remission for less
than 1 within the past 5 year. Non-melanoma skin cancers do not preclude
participation in the trial.

10. Concomitant administration of drugs known to interfere with renal excretion of
phenylacetylglutamine or those medications that may induce hyperammonemia such as
haloperidol, valproic acid and systemic corticosteroids (prohibited during the
study). Alternative ammonia modifying agents such as lactulose and rifaximin are not
considered standard of care and are prohibited during the study period.

11. Any other health condition that would preclude participation in the study in the
judgment of the principal investigator.